Hyperoxidized albumin modulates neutrophils to induce oxidative stress and inflammation in severe alcoholic hepatitis

Das, Subodh K.; Maras, Jaswinder Singh; Hussain, Md. Shabir; Sharma, Shvetank; David, Paul; Sukriti, Sukriti; Shasthry, Saggere Muralikrishna; Maiwall, Rakhi; Trehanpati, Nirupama; Singh, Tejbir; Sarin, Shiv Kumar

doi:10.1002/hep.28897

Cited by 92 publications

(90 citation statements)

References 42 publications

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“…Other SRs, such as glycoproteins 18 and 30, which avidly bind chemically modified albumin by formaldehyde or maleic anhydride, could also be candidates; but they do not signal through p38 MAP kinase . Finally, data based on changes in mRNA expression suggest that up‐regulation of several toll‐like receptors (TLRs), especially TLR5, could be involved in the response of neutrophils to oxidized albumin forms …”

Section: Discussionsupporting

confidence: 91%

“…Because plasma HNA2 levels were higher in patients with SAH than in patients with cirrhosis and healthy subjects and the in vitro effects were more evident in cells treated with albumin from patients with SAH, the authors assumed that the biological effects were due to HNA2. However, the albumin from patients with SAH contained not only HNA2 (approximately 15.5% of the total albumin) but also high quantities of HNA1 (44.5% of the total albumin) . Finally, in the current investigation, we used a concentration of 1 mg/mL of each oxidized albumin form, which is the lowest concentration identified in our cohort of patients with DC.…”

Section: Discussionmentioning

confidence: 61%

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Oxidized Albumin Triggers a Cytokine Storm in Leukocytes Through P38 Mitogen‐Activated Protein Kinase: Role in Systemic Inflammation in Decompensated Cirrhosis

et al. 2018

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Decompensated cirrhosis is characterized by exuberant systemic inflammation. Although the inducers of this feature remain unknown, the presence of circulating forms of oxidized albumin, namely human nonmercaptalbumin 1 (HNA1) and HNA2, is a common finding in cirrhosis. The aim of this study was to explore the ability of these oxidized albumin forms to induce systemic inflammation by triggering the activation of peripheral leukocytes. We observed significantly higher plasma levels of HNA1 and HNA2 in patients with cirrhosis (n = 256) compared to healthy volunteers (n = 48), which gradually increased during the course from compensated to decompensated to acute-on-chronic liver failure. Plasma HNA1 and HNA2 levels significantly correlated with inflammatory markers (i.e., interleukin-6 [IL-6], IL-1β, tumor necrosis factor-alpha [TNF-α] and IL-8) in patients with cirrhosis. To directly test the inflammatory effects of HNA1 and HNA2 on leukocytes, these oxidized albumin forms were prepared ex vivo and their posttranslational modifications monitored by liquid chromatography (LC)-quadrupole time-of-flight/mass spectrometry (MS). HNA1, but not HNA2, increased IL-1β, IL-6, and TNF-α mRNA and protein expression in leukocytes from both healthy volunteers and patients with cirrhosis. Moreover, HNA1 up-regulated the expression of eicosanoid-generating enzymes (i.e., cyclooxygenase-2 [COX-2] and microsomal prostaglandin E [PGE] synthase 1) and the production of inflammatory eicosanoids (PGE , PGF , thromboxane B , and leukotriene B ), as determined by LC-electrospray ionization-MS/MS. The inflammatory response to HNA1 was more pronounced in peripheral blood mononuclear cells (PBMCs) and marginal in polymorphonuclear neutrophils. Kinome analysis of PBMCs revealed that HNA1 induced the phosphorylation of p38 mitogen-activated protein kinase, the inhibition of which blocked HNA1-induced cytokine and COX-2 induction. Conclusion: HNA1 triggers an inflammatory response in PBMCs, providing a rationale for its removal and replacement by reduced albumin in the prevention of systemic inflammation in patients with advanced liver disease.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 61%

Oxidized Albumin Triggers a Cytokine Storm in Leukocytes Through P38 Mitogen‐Activated Protein Kinase: Role in Systemic Inflammation in Decompensated Cirrhosis

et al. 2018

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“…Finally, more conclusive evidence for an important role of neutrophils in chronic-plus-binge ethanol-induced liver injury was given by the result that depletion of neutrophils using a neutralizing antibody ameliorates liver injury in this model 18, 28 . Although we provided convincing evidence that neutrophils contribute to hepatocellular damage in the mild liver injury in these models, neutrophils likely play both detrimental and beneficial roles in the pathogenesis of severe forms of ALD, such as promoting hepatotoxicity, protecting against bacterial infection, and promoting liver regeneration 39–41 .…”

Section: New Insights Into the Underlying Mechanisms Of Chronic-plus-mentioning

confidence: 80%

Animal Models of Alcoholic Liver Disease: Pathogenesis and Clinical Relevance

et al. 2017

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Alcoholic liver disease (ALD), a leading cause of chronic liver injury worldwide, comprises a range of disorders including simple steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma. Over the last five decades, many animal models that have been useful for the study of ALD pathogenesis have been developed. Recently, a chronic-plus-binge ethanol feeding model was reported. This model induces significant steatosis, hepatic neutrophil infiltration, and liver injury. A clinically relevant model of high-fat diet feeding plus binge ethanol was also developed, which highlights the risk of excessive binge drinking in obese/overweight individuals. All of these models recapitulate some features of the different stages of ALD and have been widely used by many investigators to study the pathogenesis of ALD and test therapeutic drugs/components. However, these models are somewhat variable, depending on mouse genetic background, ethanol dose, and animal facility environment. This review focuses on these models and discusses these variations and some methods to improve the feeding protocol. The pathogenesis, clinical relevance, and translational studies of these models are also discussed.

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“…Further stressing the importance of oxidation of albumin in end stage liver disease. In human alcoholics with severe hepatitis, hyperoxidized serum albumin contributes to neutrophil activation and enhanced oxidative stress 61 . Our data combined with these previous reports support the proposition that adduction of serum proteins by lipid aldehydes and the initiation of both innate and adaptive immune response contribute to human NASH progression mimicking evidence in animal models.…”

Section: Discussionmentioning

confidence: 99%

Differential carbonylation of proteins in end-stage human fatty and nonfatty NASH

Shearn

Saba

Roede

et al. 2017

Free Radical Biology and Medicine

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Objective In the liver, a contributing factor in the pathogenesis of non-alcoholic fatty liver disease is oxidative stress leading to the accumulation of highly reactive electrophilic α/β unsaturated aldehydes. The objective of this study was to determine if significant differences were evident when evaluating carbonylation in human end-stage fatty nonalcoholic steatohepatitis (fNASH) compared to end-stage nonfatty NASH (nfNASH). Methods Using hepatic tissue obtained from healthy humans and patients diagnosed with end stage nfNASH or fNASH, overall carbonylation was assessed by immunohistochemistry (IHC) and LC-MS/MS followed by bioinformatics. Results Picrosirius red staining revealed extensive fibrosis in both fNASH and nfNASH which corresponded with increased reactive aldehyde staining. Although significantly elevated when compared to normal hepatic tissue, no significant differences in overall carbonylation and fibrosis were evident when comparing fNASH with nfNASH. Examining proteins that are critical for anti-oxidant defense revealed elevated expression of thioredoxin, thioredoxin interacting protein, glutathione S-transferase p1 and mitochondrial superoxide dismutase in human NASH. As important, using immunohistochemistry, significant colocalization of the aforementioned proteins occurred in cytokeratin 7 positive cells indicating that they are part of the ductular reaction. Expression of catalase and Hsp70 decreased in both groups when compared to normal human liver. Mass spectrometric analysis revealed a total of 778 carbonylated proteins. Of these, 194 were common to all groups, 124 unique to tissue prepared from healthy individuals, 357 proteins exclusive to NASH, 124 proteins distinct to samples from patients with fNASH and 178 unique to nfNASH. Using functional enrichment analysis of hepatic carbonylated proteins revealed a propensity for increased carbonylation of proteins regulating cholesterol and Huntington’s disease related pathways occurred in nfNASH. Examining fNASH, increased carbonylation was evident in proteins regulating Rho cytoskeletal pathways, nicotinic acetylcholine receptor signaling and chemokine/cytokine inflammatory pathways. Using LC-MS/MS analysis and trypsin digests, sites of carbonylation were identified on peptides isolated from vimentin, endoplasmin and serum albumin in nfNASH and fNASH respectively. Conclusions These results indicate that cellular factors regulating mechanisms of protein carbonylation may be different depending on pathological diagnosis of NASH. Furthermore these studies are the first to use LC-MS/MS analysis of carbonylated proteins in human NAFLD and explore possible mechanistic links with end stage cirrhosis due to fatty liver disease and the generation of reactive aldehydes.

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Hyperoxidized albumin modulates neutrophils to induce oxidative stress and inflammation in severe alcoholic hepatitis

Abstract: In patients with SAH, there is a significant increase in albumin oxidation, and albumin acts as a pro-oxidant; this promotes oxidative stress and inflammation in SAH patients through activation of neutrophils. (Hepatology 2017;65:631-646).

Cited by 92 publications

References 42 publications

Oxidized Albumin Triggers a Cytokine Storm in Leukocytes Through P38 Mitogen‐Activated Protein Kinase: Role in Systemic Inflammation in Decompensated Cirrhosis

Oxidized Albumin Triggers a Cytokine Storm in Leukocytes Through P38 Mitogen‐Activated Protein Kinase: Role in Systemic Inflammation in Decompensated Cirrhosis

Animal Models of Alcoholic Liver Disease: Pathogenesis and Clinical Relevance

Differential carbonylation of proteins in end-stage human fatty and nonfatty NASH

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